Genome-wide association study identifies the first germline genetic variant associated with Erdheim Chester disease

[Objective] Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study.[Methods] After quality controls, a cohort of 255 ECD patients and 7,471 healthy donors was included in this study. Afterwards, a logistic regression followed by in silico functional annotation was performed.[Results] A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (p-value=2.75x10-11; OR=2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.[Conclusion] Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.This work was supported by the project “Genome-wide and epigenome-wide association study in patients with Erdheim-Chester Disease”, funded by by Histio UK, and supported in part by the Intramural Research Program of the National Human Genome Research Institute and Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039). M.A.H. is a recipient of a Miguel Servet fellows hip (CP21/00132) from Instituto de Salud Carlos III. L.O.F. was supported by a Juan de la Cierva Incorporación fellowship (IJC2019-040746-I) funded by MCIN/AEI/10.13039/501100011033.Peer reviewe

Erdheim-Chester disease beyond the MAPK pathway : association with myeloid neoplasms and additional mutations, monocytes profile and T cells polarization, interaction with osteogenesis

La maladie d’Erdheim-Chester est une histiocytose du groupe L survenant principalement chez l’adulte d’âge moyen. Sa physiopathologie a récemment été éclairée par la découverte de mutations activatrices des voies signalisation intracellulaire, principalement dans la voie des MAPK dans les histiocytes pathologiques des tissus atteints. Ces découverts ont permis l’avènement de nouvelles thérapies ciblées, avec une efficacité notable. De nombreuses inconnues sur la pathogénèse de la maladie demeurent, notamment concernant le phénotype immunitaire et clinique. Dans une première partie, nous montrons que la maladie d’Erdheim-Chester est fréquemment associée aux néoplasmes myéloïdes, avec de nombreuses mutations additionnelles, ce qui témoigne d’une physiopathologie commune entre les deux pathologies. Dans une deuxième partie, nous avons mis en évidence un profil monocytaire particulier, avec une augmentation des proportions de monocytes classiques et une diminution des proportions de monocytes non-classiques, ce qui rappelle le profil monocytaire retrouvé dans la leucémie myélo-monocytaire chronique, témoignant de l’association non-fortuite des deux maladies. Nous avons également mis en évidence que les lymphocytes Th17 circulants étaient significativement augmentés et les lymphocytes T régulateurs circulants diminués. Troisièmement, nous avons mis en place un modèle murin reproduisant pour la première fois une manifestation clinique typique de la maladie, à savoir l’ostéosclérose des os longs. Nous formulons également l’hypothèse que, comme dans les néoplasmes myéloïdes, l’ostéosclérose observée est le résultat d’une dérégulation des protéines impliquées dans le remodelage osseux : ostéoprotégérine et RANK-L.Erdheim-Chester disease is an adult-onset histiocytosis of the L-group. Its pathogenesis has recently been enlightened by the discovery of several activating mutations of intra-signaling pathways in pathological histiocytes, mostly in the MAPK pathway. These discoveries led to targeted therapies, with notable efficacy. Nevertheless, Erdheim-Chester disease pathogenesis remains widely undetermined, especially regarding its immune and clinical phenotype. In the first part of this work, we showed that Erdheim-Chester disease is frequently associated with myeloid neoplasms, with many additional mutations, testifying for a common pathogenesis. In a second part, we have highlighted a specific monocytes profile, with increased proportion of classical monocytes, and decreased proportion of non-classical monocytes, which is a feature typically observed in patients with chronic myelomonocytic leukemia, suggesting a non-fortuitous association. We also showed that proportion of circulating Th17 cells was increased, whereas circulating Treg cells proportion was decreased. In a third part, we performed a xenografted mouse model who was for the first time able to reproduce a specific clinical feature of the disease: long bone osteosclerosis. We also hypothesized that osteosclerosis in Erdheim-Chester disease, as in myeloid neoplasm, results from a deregulation of osteoprotegerin and RANK-L, two proteins strongly involved in bone remodeling

Immune phenotyping of Erdheim-Chester disease through mass cytometry highlights decreased proportion of non-classical monocytes and increased proportion of Th17 cells

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Atypical ocular manifestation of primary varicella zoster virus infection as the first manifestation of AIDS

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Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells

International audienceLangerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34+ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34+ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34+ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm

High prevalence of myeloid neoplasms in adults with non–Langerhans cell histiocytosis

International audienceKey Points Some 10.1% of adults with non–Langerhans cell histiocytosis have a concomitant myeloid neoplasm with each often harboring distinct mutations. The presence of distinct kinase mutations in histiocytosis and myeloid neoplasms resulted in discordant responses to targeted therapy